Empirical Validation of a Hypothesis of the Hormetic Selective Forces Driving the Evolution of Longevity Regulation Mechanisms

Abstract

Exogenously added lithocholic bile acid and some other bile acids slow down yeast chronological aging by eliciting a hormetic stress response and altering mitochondrial functionality. Unlike animals, yeast cells do not synthesize bile acids. We therefore hypothesized that bile acids released into an ecosystem by animals may act as interspecies chemical signals that generate selective pressure for the evolution of longevity regulation mechanisms in yeast within this ecosystem. To empirically verify our hypothesis, in this study we carried out a three-step process for the selection of long-lived yeast species by a long-term exposure to exogenous lithocholic bile acid. Such experimental evolution yielded 20 long-lived mutants, three of which were capable of sustaining their considerably prolonged chronological lifespans after numerous passages in medium without lithocholic acid. The extended longevity of each of the three long-lived yeast species was a dominant polygenic trait caused by mutations in more than two nuclear genes. Each of the three mutants displayed considerable alterations to the age-related chronology of mitochondrial respiration and showed enhanced resistance to chronic oxidative, thermal, and osmotic stresses. Our findings empirically validate the hypothesis suggesting that hormetic selective forces can drive the evolution of longevity regulation mechanisms within an ecosystem.

Specific changes in mitochondrial lipidome alter mitochondrial proteome and increase the geroprotective efficiency of lithocholic acid in chronologically aging yeast

“…Purification of mitochondria [ 83 ], SDS-PAGE [ 84 ], quantitative mass spectrometric analysis of lipids [ 85 ] and statistical analysis [ 86 ] were performed as previously described. Mass spectrometric identification and quantification of proteins were performed as previously reported [ 87 ].…”

Mechanisms that Link Chronological Aging to Cellular Quiescence in Budding Yeast

“…The stimulatory effect of CR on the tolerance of NQ cells to these stresses is observed early in chronological lifespan, in the PD growth phase [ 24 ]. Of note, the longevity of chronologically aging yeast can be extended by the interventions that enhance cell tolerance to chronic thermal and oxidative stresses [ 2 , 6 , 84 , 88 , 94 , 96 , 97 , 98 , 99 , 100 ].…”

Lithocholic Acid Improves the Survival of Drosophila Melanogaster

“…Bile acids have been shown to improve the resistance to diverse stressors. It has been postulated that only in yeast strains that have developed specific defense mechanisms in response to an exposure to bile acids are able to cope with the age‐dependent increase in stress, which ultimately contributes to extend their lifespan . Interestingly, long‐lived little mice ( Ghrhrlit/lit ) have increased levels of bile acids, suggesting that bile acid signaling increases the stress‐coping capacity and consequently their life expectancy .…”